The present invention relates generally to antimicrobial agents and, in particular, to metalbased antimicrobial agents suitable for coating medical devices.
Many medical procedures involve the placement of devices, such as catheters, endotracheal tubes, protheses, grafts, sutures, dressings and implants, in the human body. Infection is a common complication associated with the use of such devices. Various techniques for alleviating infection in this regard are commonly employed, including topical and systemic applications of antibiotics. Nonetheless, such techniques have not been particularly effective in preventing infection associated with devices intended to remain within the body, or in contact with bodily fluids, for an extended period of time.
Antimicrobial agents are chemical compositions that inhibit microbial growth or kill bacteria, fungi and other microorganisms. Different inorganic and organic substances display antimicrobial activity. Among the simple organic substances that possess antimicrobial activity are carboxylic acids, alcohols and aldehydes, most of which appear to act by protein precipitation or by disruption of microbial cell membrane.
The antimicrobial activity of inorganic substances is generally related to the ions, toxic to other microorganisms, into which they dissociate. The antimicrobial activity of various metal ions, for example, is often attributed to their affinity for protein material and the insolubility of the metal proteinate formed. Metal-containing salts are thus among the inorganic substances that act as antimicrobial agents.
Metal inorganic salts, including simple salts of metal cations and inorganic anions like silver nitrate, are often soluble and dissociable and, hence, offer ready availability of potentially toxic ions. But such salts may be quickly rendered ineffective as antimicrobial agents by the combining of the metal ion with extraneous organic matter or with anions from tissue or bodily fluid. As a consequence, prolonged or controlled bacteriostatic and bacteriocidal activity is lost.
Metal salts or complexes of organic moieties such as organic acids, on the other hand, are often less soluble and, therefore, are less dissociable than the soluble metal inorganic salts. Metal organic salts or complexes generally have a greater stability with respect to extraneous organic matter, and anions present in the environment of the living cell than metal inorganic salts, but have less toxic potential by virtue of their greater stability. The use of heavy metal ions with polyfunctional organic ligands as antimicrobial agents has been disclosed, for example, in U.S. Pat. No. 4,055,655.
The silver (I) ion is an example of a metal ion known to possess antimicrobial activity. The use of silver salts, including both inorganic and organic ligands, as antimicrobial agents has long been known in the prior art. The dissociation of the silver salt provides silver ions which provide the antimicrobial activity. Silver ions react with a variety of anions as well as with chemical moieties of proteins. Precipitation of proteins, causing disruption of the microbial cell membrane and complexation with DNA, is likely the basis of the antimicrobial activity. Silver ions in high concentration will form insoluble silver chloride and thereby deplete chloride ions in vivo.
Silver sulfadiazine is an organo-silver salt which is currently widely used as a topical antimicrobial agent, as discussed by Fox, "Silver Sulfadiazine - A New Topical Therapy for Pseudomonas in Burns," Archs. Surg. 96: 184-88 (1968). The antimicrobial activity of silver complexes with fatty acids has also been disclosed, for example, in U.S. patents No. 3,255,222 and No. 3,385,654.
But silver salts, like a number of other metal salts, are also light sensitive, in that exposing them to light causes a discoloration or black staining associated with the deposition of reduced silver. Silver salts are usually most sensitive to blue light or higher energy electromagnetic radiation such as ultraviolet rays.
Both the antimicrobial activity and the light stability of a silver salt are dependent upon its stability and solubility. In general, a large dissociation constant generally leads to discoloration, while a small dissociation value leads to minimal growth inhibition or toxic potential due to the low concentration of available silver ions.
High solubility also promotes discoloration or black staining. Low solubility, on the other hand, results in a low availability of silver ions. Thus, it appears likely that a silver salt with a low solubility and a medium-range dissociation constant will be light stable.
In general, prior attempts at the use of antimicrobial metallic compositions, including silver salts, appear to have encountered problems of two types. On the one hand, there are metal compounds that have a high degree of dissociation such that toxic metal ions are rapidly and copiously made available, due to rapid dissociation and consequent formation of ionized species. These species saturate all available ligands and are thereby inactivated in a very narrow time frame. This obviates residual killing power, rendering such compositions relatively ineffective as antimicrobial agents over prolonged periods of time. On the other hand, metal compounds which are relatively stable provide only minimal amounts of ionized species over the normal physiological pH range. They provide, therefore, minimal growth inhibition or toxic potential, due to their low degree of dissociation.
The use of metal-based antimicrobial compositions applied as coatings on medical devices poses further problems. The matrix in which the antimicrobial agent is held to form the coating must be permeable to allow diffusion of the antimicrobial metal ions out of the matrix in to the environment. The solubility of the antimicrobial agent in a suitable solvent must be sufficient so that the resulting coating has a concentration of agent which will yield antimicrobial activity.
If the solubility is very low, a coating with a large surface area may be required to obtain an active amount of antimicrobial agent. A thicker antimicrobial coating, for example, of greater than 1 mm in thickness, may be required to obtain an active amount of antimicrobial agent. The dissociation of the metallic and the diffusion rate of the metal ions out of the matrix, i.e., the release of ions, must correspond to the medical use of the device. For devices that will be in contact with the body for extended times, a slow, steady release of metal ions would be appropriate. For devices with a short lifetime, quicker release may be most appropriate.
If a silver-based compound is to be used, it must not undergo chemical reaction upon exposure to light or, at least, the rate of such a photoreaction must be slow compared to the duration of contact between the medical device and body tissue or fluid. Also, the available silver ion concentration should not be so high as to deplete chloride from the environment.
The use of silver sulfadiazine in this context is of particular interest since both the silver ion and the sulfadiazine one of the sulfonamides or "sulfa" drugs, have antimicrobial properties. Silver sulfadiazine is a polymer wherein each silver ion is tetracoordinated and surrounded by three different deprotonated sulfa molecules; each sulfa molecule, in turn, binds three different silver ions. See Bult, "Silver Sulfadiazine and Related Antibacterial Metal Sulfanilamides; Facts and Fancy," Pharmacy Intl. December, 1982, at pages 400-04.
Silver sulfadiazine is formed by combining equal molar amounts of silver nitrate and sodium sulfadiazine solutions. Its dissociation constant (pK) is 3.57 at a pH of 7.4, an ionic strength of 0.1 and a temperature of 25.degree. C. The compound is almost insoluble in water and in organic solvents, a feature attributable to its polymeric character. It does not darken upon exposure to light and does not deplete chloride from tissue fluid. It is likely that its insolubility and medium-range stability constant are responsible for photostability and lack of chloride depletion.
But low solubility can result in minimal toxic potential to microbes. The very low solubility of silver sulfadiazine also limits its incorporation into synthetic or natural polymeric materials. Multiple layers of coatings are generally required to achieve a sufficient amount of the silver sulfadiazine for antimicrobial activity.
Despite many prior attempts at imparting antimicrobial properties to medical devices, a coating composition has yet to be demonstrated that provides for variation in the release of antimicrobial agent, according to the particular use of the medical device, and for sufficient solubility to allow the use of thin coatings.